Penicillin salt of alpha-phenyl-beta-n-amylaminoethyl chloride



United States Patent PENICILLIN SALT OF 02- HEN L-fi-n-AMYL- ANHNOETHYL CHLORIDE Frank H. Buckwalter, Dewitt, and Alphonse P. Granatek, Syracuse, N. Y., assignors to Bristol Laboratories Inc., Syracuse, N. Y., a corporation of New York No Drawing. Application March 13, 1952, Serial N 276,454

2 Claims. (Cl. 260-239.1)

The present invention relates to a new, non-toxic, waterinsoluble, amine salt of penicillin, more particularly a penicillin salt of a-phenyl-fl-n-arnyl-aminoethyl chloride, which is capable of exerting a repository antibiotic action and is also useful for oral, therapeutic administration and for external application and for use as a supplement in animal and poultry feeds.

The new penicillin salt of the present invention has the following formula I Cl wherein Pen designates an acid penicillin radical or an active moiety thereof, capable of forming an addition salt with a-phenyl- 3n-arnyl-aminoethyl chloride. The product of the present invention may be obtained by reaction of penicillin acid with aphenyl-}8-n-amylaminoethyl chloride in a water-immiscible organic solvent and by the metathetical reaction of a water-soluble penicillin salt and a water-soluble salt of a-phenyl-;8-n-amylaminoethyl chloride in water.

A more comprehensive understanding of this invention is obtained by reference to the following examples.

EXAMPLE I Alpha phenyl beta-n-amylaminoethyl chloride hydrochloride A solution of 30 g. (0.145 mole) of a-phenyl-B-n-amylaminoethanol in 150 cc. benzene was added dropwise to an ice-cold, stirred solution of 27.5 g. (0.23 mole) of thionyl chloride in 50 cc. of ether over a period of thirty minutes. The mixture was allowed to come to room temperature and was then refluxed for three hours. The benzene, excess thionyl chloride and gases were removed by distillation under reduced pressure on the steam bath. Twice an additional portion of 100 cc. benzene was added to the residue and removed in the same fashion. The black, solid residue of crude a-phenyl- ,B-n-amylaminoethyl chloride hydrochloride was recrystallized five times from methyl isobutyl ketone with the use of decolorizing charcoal to give a crystalline product melting at about l49l50 C.

Analysis.Calculated for CisHziClzN: C, 59.54; H, 8.07; N, 5.34. Found: C, 59.5; H, 8.09; N, 5.38.

The product is soluble in water and alcohol, moderately soluble in acetone, slightly soluble in cold methyl isobutyl ketone and insoluble in ether.

2,721,194 Fatented Got. 18, 1955 EXAMPLE I:

Penicillin G salt of alpha-phenyl-beta-n-amylaminoethyl chloride 0.144 gram of a-phenyl-fi-n-amylaminoethyl chloride hydrochloride in 4.4 cc. of water is added to 0.198 gram of sodium penicillin G in 6 cc. of water. Upon scratching and cooling, the crystalling penicillin G salt of aphenyLB-n-amylarninoethyl chloride precipitates and is collected by filtration. This salt has a potency of about 1060 units/mgm. and is soluble in water at room temperature to the extent of about 450 units/cc.

EXAMPLE III Potassium penicillin G (18.6 g.; 0.5 mole) is shaken with ml. of 8.5% phosphoric acid and 150 ml. of ether in the cold until two clear layers result. The aqueous layer is withdrawn and discarded. The ether solution is filtered and then added all at once to a cold solution of 0.04 mole (9 grams) of freshly liberated a-phenyl-fl-namylaminoethyl chloride in 50 ml. of ether. Crystalline penicillin G salt of aphenyI-B-n-amylaminoethyl chloride precipitates and is collected by filtration.

While the present invention has been described with particular reference to the a-phenyl-fl-n-amylaminoethyl chloride salt of penicillin G it will be understood that the a-phenyl-B-n-arnylaminoethyl chloride salts of other penicillins are also included within the scope of this invention. For instance, penicillins such as the penicillins G, F, X, dihydro F, O and K and mixtures of two or more such penicillins, particularly such mixtures containing at least of penicillin G, are included within the scope of this invention.

It will be understood that the reaction can be carried out in water-immiscible organic solvents other than ether. Examples of such solvents are butanol, amyl acetate, methyl amyl acetate, isopropyl ether, mesityl oxide, methyl isobutyl ketone, methylene dichloride, ethylene dichloride and chloroform. Recovery of the product may be increased by evaporating the solvent in vacuo at low temperatures.

It will be understood also that the ethereal solution of the free base may be prepared in ether by the use of caustic to liberate the free amine from an organicsolvent soluble or water soluble salt such as the hydrochloride, phosphate, nitrate, hydrobromide, sulfate, citrate, acetate and tartrate.

It will be understood that, without departing from the spirit of the invention or the scope of the claims, various modifications may be made in the specific expedients described as these are illustrative only.

We claim:

1. A salt of penicillin and a-phenyl-B-n-amylaminoethyl chloride.

2. A salt of penicillin G and a-phenyl-B-n-amylamino ethyl chloride.

References Cited in the file of this patent UNITED STATES PATENTS 2,547,640 Goldman Apr. 3, 1951 2,578,641 Cooper Dec. 11, 1951 2,598,508 Cooper May 27, 1952 2,654,746 Rhodehamel Oct. 6, 1953 

1. A SALT OF PENICILLIN AND A-PHENYL-B-N-AMYLAMINOETHYL CHLORIDE. 